TW201217366A - Aprepitant L-proline composition and cocrystal - Google Patents

Abstract

A 1: 1: 1 aprepitant L-proline H2O composition and a 1: 1: 1 aprepitant L-proline H2O cocrystal are disclosed as well as pharmaceutical compositions containing a 1: 1: 1 aprepitant L-proline H2O composition or cocrystal and a pharmaceutically acceptable carrier. The 1: 1: 1 aprepitant L-proline H2O composition or cocrystal may be used in the same way as aprepitant to treat or prevent disorders relating to emesis, a neuropsychiatric disease, an inflammatory disease, pain, cancer, a skin disease, itch, a respiratory disease, or an addiction.

Description

201217366 VI. Description of the invention: [Technology of the invention] The cross-reference to the relevant application claims the priority of the US application number 61/385,744 filed on September 23, 2010; the claim is February 4, 2011 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; data. FIELD OF THE INVENTION The present invention relates to a novel aprepitant composition and a crystalline compound containing aprepitant; more particularly, the present invention relates to an aprepitant L-oxime Therapeutic use of an amino acid composition, an aprepitant L-proline eutectic crystal, aprepitant L-proline or aprepitant l-valine co-crystal and containing a kind of aprepitant a pharmaceutical composition of crystals. C Prior Art 3 Background Cancer patients generally experience nausea and vomiting during disease progression and treatment. Nausea and/or vomiting may be the result of the cancer itself or its treatment. Ari-bitan is 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- (4-fluoro)-phenyl-4-(3-(5-sideoxy·1H,4H-1,2,4-triazole)methylporphyrin, a substance P/neurokinin type 1 ( NK1) receptor antagonists for the prevention of acute and delayed nausea associated with vomiting and moderate and highly vomiting chemotherapy and for the prevention of postoperative nausea and vomiting (PONV).

The neuropeptide of substance P (neurokinin type 1: Ν Κ -1) is involved in the nervous system, circulatory system and surrounding tissues of mammals, and regulates several biological processes, including olfactory, visual, pain, Sensory perception of vasodilation, gastric peristalsis, and motion control "The effects of substance p antagonists on neuropsychiatric disorders, inflammatory diseases, pain (including migraine), skin diseases, asthma and other respiratory diseases, and vomiting are being investigated. The substance p is also known as a major mediator of itchy skin itching. Studies have reported that aprepitant, a substance P antagonist, may be effective in treating skin itching (S. StSnder in the 201st issue of the journal PLoSOne, page 5 (6), e 10968) The target of the neurokinin Receptor 1 with aprepitant: a novel antipruritic strategy (B). Types of itching or skin irritation include, but are not limited to: a) psoriasis skin itching, itching due to dialysis, watery skin pain and skin disorders (such as contact dermatitis), systemic disorders, neuropathy 'pruritus caused by psychogenic factors or a combination thereof; b) itch caused by allergic reactions, insect bites, allergies (such as dry skin, acne, moist treatment, psoriasis), inflammatory conditions or injuries; c) itch associated with vulvar vestibulitis; and d) skin irritation or 201217366 inflammatory effects due to administration of another treatment such as, for example, antibiotics, antiviral drugs and antihistamines. The NK1 receptor has been shown to be overexpressed in a wide range of tumor cells, and the binding of NK1 receptor antagonists such as aprepitant to these receptors has been shown to inhibit tumor cell proliferation, angiogenesis, and tumor cell migration. Intra-experimental studies have shown the utility of A. D. battan in several cancer cell lines including malignant melanoma, neuroblastoma, pancreatic cancer, gastric cancer, and colon cancer cell lines. These studies indicate the potential of aprepitant as a broad-spectrum anti-tumor drug (M. Mufioz. in the April 2010 issue of Invest New Drugs, Vol. 28(2), pp. 187-93. "The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug" B) The substance P involves stress-responsiveness and reward-related behavior ( PW Mantyh in the 1987 issue of "Brain Research" No. 307, pp. 147-165, B). Current clinical trials are exploring whether aprepitant, a substance P antagonist, may have a positive effect on the cravings and dependence associated with addictive substances such as alcohol, coca, opium, marijuana and tobacco. The Biopharmaceutics Classification System (BCS) classifies aprepitant as a Class IV drug, indicating that it is an API with low solubility and low permeability. APIs that are not water soluble are typically characterized by low absorption and inability to bioavailability. Aprepitant is a white to off-white crystalline solid which is slightly soluble in acetamidine and isopropyl acetate, slightly soluble in acetonitrile, but is practically insoluble in water. Aprepitant is recognized by CAS Registry Number 17〇729-80-3. Ari Bibitan, along with its preparation methods, is disclosed in PCT Application WO 95/16679. See also 5, 2012, 366, see US Patent Nos. 5,719,147, 6, 859, 859, and 6,235,735. U.S. Patent No. 6,096,742 describes the polymorph of aprepitant. It is currently approved for the prevention of nausea and vomiting associated with chemotherapy and for the prevention of post-operative nausea and vomiting. It is marketed by Merck as an oral capsule containing 4 mg, 80 mg and 125 mg of aprepitant. The aprepitant developed by the company is currently marketed as a nanoparticle formulation to overcome its poor solubility/pollution properties. See, for example, U.S. Patent No. 5, No. 45,684. But even with nanoparticle formulations, the average absolute bioavailability of aprepitant is only 60 to 65%. There is therefore a need to develop new aprepitants with solubilization, solubility improvement, and/or increased bioavailability. The aprepitant composition and the eutectic system of the present invention should be equivalent. Although the primary concern of the active pharmaceutical ingredient (A PI) is in the therapeutic efficacy, the salt and solid form (ie, crystalline or amorphous form) of a drug candidate can be related to its pharmacological properties such as bioavailability, and Shaoguan has become a viable API research and development work. Recently, the crystal form of the API has been used to change the physicochemical properties of a particular API. Each crystal form of a candidate drug can have different solid (physical and chemical) properties. A difference between the physical properties exhibited by a novel solid form of the API (such as a eutectic or polymorph of the original therapeutic compound), the pharmacological parameters such as storage stability, compressibility and density (in the ligand) It is important in terms of manufacturing aspects of the product) and the solubility and dissolution rate (an important factor in determining bioavailability). Since these actual physical properties are affected by the solid state properties of the API crystal form, they can significantly affect the selection of a compound as an API, the final pharmaceutical dosage form, and the process optimization effect 201217366 and in vivo absorption (4). In addition, finding the most appropriate form can reduce the time and cost of the development. The development of the pair is very important in the development of the pair. It may be caused by ==4 quality, micro-analysis. There are also 4 kinds of API co-crystals and _ kinds of conformations: the second (four) enamel state of the free test. As with the eutectic of the present invention, these two properties may be more advantageous than the known form of the api itself: easy processing. For example, the lytic properties of the eutectic may be different from the API itself and may be used in the treatment of ^1. The new mash composition containing a particular api has the property 'being better than its existing pharmaceutical formulation. They can also have better storage stability.八—ΑΠ的— a potentially important solid state f is the rate of dissolution of the compound in the aqueous solution of the compound in the aqueous liquid. The rate of dissolution in the gastric juice may have therapeutic consequences, as it affects the oral administration. The active ingredient can reach the rate of the patient's gold flow. - An API eutectic system - a unique chemical composition of the Αρι and the conformation, and generally unique crystallography and spectroscopy when compared with the individual of the API and the conformation (4). In addition to its reduction, the crystallographic and spectroscopic properties of the crystal form are typically measured by X-ray powder diffraction (XRPD) and single crystal X-ray crystallography. Co-crystals also typically exhibit unique thermal behavior. Thermal behavior was measured experimentally by techniques such as capillary melting point, thermogravimetric analysis (TGa), and differential scanning calorimetry (DSC). 7 201217366 C SUMMARY OF THE INVENTION The present invention relates to a 1:1:1 aprepitant L-proline hydrate composition and a 1:1:1 aprepitant L-proline acid water Co-crystals, as well as pharmaceutical compositions containing them and a pharmaceutically acceptable carrier. The eutectic has a dissolution rate superior to that of aprepitant. The 1:1:1 aprepitant L-proline aqueous composition and co-crystals can be used to treat or prevent vomiting, a neuropsychiatric disorder, an inflammatory disease, in the same manner as aprepitant. , pain, cancer, a skin disease, itching, a respiratory disease or an addiction-related condition. A brief description of the diagram Figure 1 shows Ari at 1:1:1. XRPD pattern of Bittan L-Acetate water co-crystal. The second figure shows the 1:1 of the heart of the coffee, the surface of the acid, the celestial body of the celestial body, and the ORTEP figure of 100K. Figure 3 shows a 1:1:1 ORTEP plot of 100K.

Molecular B of resorcinol L-proline acid water co-crystal Figure 4 shows a 1:1:1 K-stacking pattern. Repeptide L-proline acid water co-crystal in ιοοκ Figure 5 shows a 1:1:1 蚪 calculated XRPD pattern 瑞0 坦坦 L-proline water eutectic in 1 οοκ Figure 6 shows 1 : 1:1 of the ORTEP diagram.

Rui. Bittan L-proline acid water co-crystals at 294K Figure 7 shows a 1:1:1 stack of corioprotan L-proline acid water co-crystals at 294 Κ 201217366. The XRPD pattern calculated from the octopus L-proline acid water co-crystal at 294K in IX.

Figure 9 shows the DSC trace of the eu:1:ι Ari beta-Butan L_amino acid water co-crystal. Figure 10 shows the TGA trace of a 1:1:1 Ari-Otan Tan L-face acid eutectic. Fig. 11 shows the 1H 1SHVIR spectrum of the erbium citrate [_ valine acid water eutectic crystal of 1··1·1. Figure 12 shows the 13C solid state NMR spectrum of a 1:1:1 Ade-Tentan L_proline acid water co-crystal recorded using dipole phase desorption. Figure 13 shows Ari at 1:1:1. Bitan L-proline acid water co-crystals and crystals Ari-Bibitan has an average dissolution profile during the head # of the steamed towel with 2.2% SDS. Figure 14 shows an overlay of XRPD patterns at different time points during a 6-month accelerated stability study of a 1:1:1 aprepitant L-proline aqueous eutectic at 4 mouth 75% relative humidity. . [Embodiment 3] Detailed Description The present invention relates to Ari. The physicochemical and/or pharmaceutical properties of Bittan are improved. Here, a novel Ari-Bitan composition, a 1:1:1 aprepitant L-proline hydrate and aprepitant-type co-crystals, a species 1:1:1 The Ari (Tan L_脯 bribe eutectic boat. The dissolution rate of the eutectic is better than that of the crystal, Ruijian, to make nai green particles. The therapeutic use and inclusion of the 201217366 repyridamine co-crystal The therapeutic composition of the eutectic is as follows. The eutectic and the method for performing its characteristic analysis are as follows. Therapeutic use of aprepitant composition and co-crystals The present invention further relates to the present invention. Co-crystals of rubetan and eutectic, 1:1:1 aprepitant L-proline hydrate co-crystals for treating or preventing vomiting and therapeutic use of vomiting and/or nausea as described above. Repyridam compositions or co-crystals can also be used to treat neuropsychiatric disorders, inflammatory diseases, pain (including migraine), cancer, skin diseases, itch, asthma and other respiratory diseases, addiction disorders such as those discussed above, such as s sinister wine. Therefore, the present invention relates to a method of treating the condition, the steps This comprises administering to a patient in need a therapeutically effective amount of a 1: 1:1 aprepitant L-proline water, or administering to a patient in need thereof an aprepitant composition comprising the present invention Or a therapeutic composition of one of the eutectics. The term "therapeutic effect" or "treatment" refers to any therapeutic effect of a condition or disorder in a mammal, including: prevention or protection from the condition or condition, Even if the clinical symptoms do not occur; inhibiting the condition or disorder, ie preventing or inhibiting the occurrence of clinical symptoms; and/or alleviating the condition or disorder (including alleviating the discomfort associated with the condition or disorder), even clinical symptoms Dissipated. Skilled human technologists will understand that it is not always possible to distinguish between “prevention” and “inhibition” because the final one or more sensory events may be unknown, latent, or the patient is not sure until the one or more The event has occurred for a long time. Therefore, the term “prevention” as used herein is intended to be an element of “treatment” and covers both “prevention” and “inhibition” of the condition or condition. Paul 10 2012 17366 蒦 蒦 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , A η1:1 aprepitant L-proline aqueous composition or co-crystal and a pharmaceutically acceptable carrier (also referred to as a pharmaceutically acceptable excipient). The pharmaceutical composition is therapeutically suitable for the treatment or prevention such as vomiting, a neuropsychiatric disorder, an inflammatory disease, pain, cancer, a skin disease, itching, a respiratory disease or an addiction as discussed above. A disease-related disorder. A pharmaceutical composition of the present invention may be any pharmaceutical form containing a water composition or co-crystal of aprepitant L-proline as in the 1:1:1 of the present invention. It may be a tablet, a capsule, a liquid suspension, an injection, an external preparation or a patch. Ari containing 1:1:1 of the present invention can be prepared. A liquid pharmaceutical composition of Bittan L-proline hydrate. The pharmaceutical composition typically contains, for example, from about 1% to about 99% by weight of a 1:1:1 1:1 aqueous solution of Aribibitan L-valine, or a co-crystal, and, for example, 99% to 1% by weight. At least one suitable pharmaceutical excipient. In one embodiment, the composition can be between about 5% and about 75 weight. /. Between the 1st, 1st, and 1st of the present invention. The bittan L-proline aqueous composition or co-crystal&apos; and the remainder are at least one suitable pharmaceutical excipient or at least one other adjuvant as described below. "The therapeutically effective amount of a 1:1:1 aprepitant L-proline aqueous composition or eutectic according to the present invention" corresponds to about 25 to about 250 mg of Ari. Betan itself. For example, Merck sells 40 mg, 80 mg and 125 mg of Ari 11 Butan capsules or 115 mg of 201217366 injections under the Menend® trademark. Emend® products are prescribed to prevent first-day heart and vomiting associated with chemotherapy, and to prevent late-onset chewing that can occur after 5 days of treatment. A typical dose is about 125 mg administered one hour before the first day of chemotherapy and 80 mg one hour before the second and third days of chemotherapy. EMEND® prescription information. The actual dose required to treat any particular condition or disorder or any particular patient' may depend on a variety of factors, including, for example, the condition being treated and its severity; the particular pharmaceutical composition employed; the age of the patient , weight, overall health, gender and diet; mode of administration; time of administration; route of administration; and rate of excretion of aprepitant; duration of treatment; any drug combined with or used with a particular compound used; These factors are well known in the art. These factors are discussed in McGraw-Hill Publishing Company in 2001 and by Goodman and Gilman, edited by a. Gilman, J. Hardman and L. Limbird, "Therapeutic Pharmacology Foundation (The Pharmacological Basis of Therapeutics), 10th Ed., pp. 155-173, which is incorporated herein by reference. Depending on the type of pharmaceutical composition, the pharmaceutically acceptable carrier can be selected from any of the carriers or combinations thereof known in the art. The choice of pharmaceutically acceptable carrier will depend on the form of the agent and the method of administration desired to be employed. In the case of a pharmaceutical composition of the present invention, i.e., a 1:1:1 Aprepitant L-valine aqueous eutectic of the present invention, a carrier which maintains the crystalline form should be selected. In other words, the carrier should not significantly alter the 1:1:1 aprepitant L-prolinate water co-crystal. The carrier should also not be incompatible with the 1:1:1 aritipide L-proline aqueous eutectic used in other cases, such as by producing undesirable

12 201217366 The effect of the substance or in other cases interacts in a harmful manner with any other component of the pharmaceutical composition. Because, as shown in the dissolution study below, the 1:1:1 aprepitant L-proline aqueous eutectic crystal will remain in solution once dissolved without the reprecipitation of aprepitant, the present invention The 1:1:1 aprepitant L-proline hydrate composition can be used to prepare a liquid formulation of aprepitant. The pharmaceutical compositions of the present invention can be prepared by methods known in the art of pharmaceutical formulation, for example, see Remington's Pharmaceutical Sciences, 18th Edition (Mack, Easton, Pa., USA). The publishing company was published in 1990), which is incorporated herein by reference. In a solid dosage form, a 1:1:1 aprepitant L-proline aqueous co-crystal can be blended with at least one pharmaceutically acceptable excipient such as, for example, sodium citrate or dicalcium phosphate or ( a) a filler or extender such as, for example, starch, lactose, sucrose, glucose, mannitol, and citric acid; (b) a binder such as, for example, a cellulose derivative, starch, alginate, gelatin, polyethylene beta ratio (c) a humectant such as, for example, glycerin; (d) a disintegrating agent such as, for example, agar, calcium carbonate, horseberry or tapioca starch, alginic acid, crosslinked carboxymethyl group Cellulose sodium, complex citrate and sodium carbonate; (e) solution blockers such as, for example, paraffin wax; (1) absorption accelerators such as, for example, quaternary compounds; (g) humectants such as, for example, cetyl alcohol and mono-hard a fatty acid glyceride, magnesium stearate or the like; (h) an adsorbent such as, for example, kaolin and bentonite; and (丨) a lubricant such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol. , sodium lauryl sulfate or a mixture thereof. In the case of capsules, binders and pills, the dosage form may also contain a leveling agent. Other formulations suitable for oral administration may be in the form of discrete units such as capsules, sachets or lozenges; in the form of powders 201217366 or granules; in a liquid or nonaqueous liquid such as ethanol or glycerol In the form of a liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Pills, papers or pastes may also be relevant. Suitable oils may be edible oils such as cotton sesame oil, sesame oil, coconut oil or peanut oil. Dispersing or suspending agents suitable for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, gum arabic, polyglucose, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropyl Methylcellulose, hydroxypropylcellulose, carbonier and polyvinylpyrrolidone. In the pharmaceutical composition of the present invention, a pharmaceutically acceptable adjuvant known in the art of formulating a pharmaceutical preparation can also be used. These include, but are not limited to, preservatives, wetting agents, suspending agents, sweeteners, flavoring agents, aromatizing agents, emulsifying agents, and dispersing agents. It can be prevented by the action of microorganisms by incorporating an antibacterial agent and an antifungal agent such as p-hydroxybenzoic acid, gas butanol, porphyrin, sorbic acid or the like. Including isotonics such as sugars, sodium vaporification, etc. It may also be desirable. Right need 'the pharmaceutical composition of the present invention may also contain a small amount of auxiliary substances such as wetting or emulsifying agents, pH buffers, antioxidants, and the like, such as, for example, citric acid 1 sorbic stalks, three Ethanolamine oleate, butylated hydroxymethyl stupid and the like. The solid dosage form as described above can be prepared with a mold and shell, such as the hearing and the others as is well known in the art. The material may contain a bulking agent and may also be a component that is surfaced in a delayed manner - such active compound or compound. A non-limiting example of (iv) human composition is available. The hybrid (4) may be in the form of a microcapsule, and if appropriate, may have one or more of the above-mentioned excipients. 14 201217366 Suspensions may contain suspending agents other than the active compound, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, aluminum hydroxide. , bentonite, agar and mixture of gum tragacanth or sputum and the like. The liquid dosage form can be aqueous and can contain a pharmaceutically acceptable solvent and conventional liquid dosage form excipients known in the art including, but not limited to, buffers, flavoring agents, sweeteners, preservatives, and stabilizers. By using a 1:1:1 aprepitant L-proline aqueous eutectic with a normally non-irritating flaring agent or carrier such as a conventional, w-solid, but liquid at body temperature, such as A composition for rectal administration such as a suppository is prepared by mixing cocoa butter, polyethylene glycol or a wax, and thus the active ingredient described herein is released in a suitable body cavity. Compositions suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, gels, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments, pastes or foams. Or a solution or suspension as known in the art, such as a drop. Where the compositions of the present invention are intended for topical administration, the carrier may suitably comprise a solution, emulsion, ointment or gel base. The carrier or substrate may, for example, comprise at least one of the following: stone loam, lanolin, polyethylene glycol, bee mites, mineral oil, diluents such as water (tetra) and emulsifiers and ampoules (4). Zengfu may be present in a pharmaceutical composition towel for administration to the local government. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. The topical formulations may contain a concentration of the compound of the invention of from about 1 to about 1% by weight per volume (weight per unit volume). Since the 1:1:1 aprepitant L_proline water is maintained for a total of 15 201217366 crystals during the preparation, the pharmaceutical composition of the present invention is preferably a solid dosage form. Solid dosage forms for administration by mouthwash may be used, including capsules, granules, pills, powders and granules. In such solid dosage forms, the active compound may be in admixture with at least an inert, pharmaceutically acceptable excipient (also referred to as a carrier on an acceptable basis). The 1:1:1 arritzidine L-amino acid aqueous composition and co-crystals of the present invention can also be used to formulate liquid or injectable pharmaceutical compositions. The administration of a 1:1:1 arsentan l__ acid compound or co-crystal in a pure form or in a suitable pharmaceutical composition may be carried out by providing a similarly useful administration or (4) . Thus, the administration can be, for example, oral, semi-solid, oral, buccal, nasal, parenteral (intravenous, intramuscular or subcutaneous), topical, transdermal/intravaginal, intravesical, systemic or rectal. &amp;, a cold 4 dry powder or a liquid dosage form such as, for example, a keying agent, a pill, a soft elastic and hard gelatin capsule, a powder, a solution, a suspension or a gasification spray or the like, such as, for example, A unit dosage form suitable for a precise dosage of a simple pharmaceutical agent can be a convenient daily administration mode for oral administration. EXAMPLES The characteristic analysis of the 1:1:1 arubetantan 1_proline aqueous eutectic of the present invention was carried out using the following knife-out method: X-ray powder diffraction characteristic analysis: using CuKa radiation (40 kV, Sample 40 of 40 mA), Θ-2Θ goniometer, V4 receiving slit, a 锗 monochromator and a Lynxeye detector on the Bmker £8 diffractometer Light powder diffraction pattern. The performance of the instrument was tested using a certified Corundum 201217366 (Corundum) standard (nist 1976). Use the spokes to be 0.05. 2 Θ and each step time is 0_5 seconds at 2. The range of angles up to 42. 2 ' collects data at ambient temperature. A sample in the form of a plate sample operating under ambient conditions was prepared using the unground powder received. Approximately 35 mg of the sample was gently loaded into a chamber cut into a polished, zero background (51 inch) wafer. All samples were analyzed using Diffrac P/ms EVA version 11.0.0.2 or 13.0.0.2. Single Crystal X-Ray Diffraction (SCXRD): A supernova double source (SuperNova Dual source), zero-valent copper, and an Atlas (with Cryosystems Cryostream) cooling unit in Oxford (Oxford) Atlas) CCD diffractometer collects data. Use the Bruker SHELXTL program to parse the structure and refine it with the SHELXTL program that is part of the Brooke SHELXTL package. Unless otherwise stated, the hydrogen atoms attached to the carbon are placed geometrically and allowed to be refined with a transversely isotropic displacement parameter. The hydrogen atoms attached to the heteroatoms are located in a differential Fourier synthesis and are allowed to be freely refined with an isotropic displacement parameter. Thermal Analysis - Differential Scanning Calorimetry (DSC): DSC data was collected on a Q2000 from TA Instruments, equipped with a 50-bit autosampler. Use sapphire for heat capacity correction and certified indium for energy and temperature correction. Typically, _8 to 12 mg of each sample in a pinhole-shaped aluminum pan was heated from 25 ° C to 350 ° C at HTC/min. A 50 ml/min dry nitrogen purge was maintained over the sample. The instrument control software is Advantage version 2.8.0.392 and Thermal Advantage 17 201217366 4.8.3 for the q series. All data were analyzed using Universal Analysis version 4.3A software. Thermogravimetric Analysis (TGA): TGA data was collected on a Q500 TGA from TA Instruments, equipped with a 16-bit autosampler. Calibrate the temperature of the instrument with certified Alumel. Typically, 5 to 30 mg of each sample was loaded into a pre-tearened platinum crucible and an aluminum DSC pot and heated from ambient temperature to 350 ° C at 1 ° C/min. A nitrogen purge of 60 ml/min was maintained above the sample. The instrument control software is Advantage version 2.8.0.392 and Thermal Advantage version 4.8.3 for the Q series. Solution Proton NMR: 1 Η-NMR spectra were recorded on a Bruker 400 mHz spectrometer equipped with an autosampler and controlled by a DRX400 console. The sample was dissolved in DMSO to allow analysis. Data were obtained using a standard Bruker loading experiment using IC0N-NMR version 4_〇.4 (Construction 1) operating with T〇pSpin 3rd Edition (plug-in level 8). Water was determined by Karl Fischer titration (KF): using Hydranal Coulometric AG reagent with argon purge on a Mettler T〇led〇 DL39 coulomb counter, The water content of each sample was measured. A weighed solid sample was added to a container on a platinum TGA pot that was connected to a stopper to prevent water from penetrating. A sample of about 1 mg was used for each titration, and three replicate measurements were performed. 13C solid state NMR: 3C NMR spectra were obtained at ambient temperature using a Varian VNMRS spectrometer operating at i〇〇56 MHz for i3c and a 6 mm (rotor outer diameter) magic angle rotation probe. A proton-coupled orthogonal polarization magic angle rotation experiment was performed and the spectra were taken at ambient temperature under conditions of recirculation for 35 seconds, contact time 201217366 5 ms, and rotation rate 6_8 KHz. Use a depolarization delay of 50 microseconds for "dipole dephasing, optical read editing, and record the spectrum. The spectrum is referenced to the anhydrous tetrakisal group; 5 shochu (by setting the high frequency line from the diamond to 38.5 ppm) Stability Study X-ray powder diffraction characteristics analysis: using CuKa radiation (45 kV, 40 mA) 'Θ-Θ goniometer, focusing mirror, divergence slit (1/2 inch), X-ray powder diffraction pattern is collected at a specified time point on a P-spinning diffractometer of a incident beam and a divergent beam (4 mm) and a PIXcel detector. The software used for data collection is x, Pert Data Collector Version 2.2f' and the data is published using the x'pert Data Browser, page 2d. The same batch of programs for sample analysis is used below, using a standard of sulphur and benzoic acid. The instrument is verified by the instrument. The sample is operated under ambient conditions and analyzed using the powder as received by the transfer foil XRPD. About 2 to 5 mg of the sample is placed on the polyimide film (( A 96-position sample supported by Kapton and 12.7 microns thick On the board, the plate's degree (Z) is set to 9 mm. In the range of 3 to 40. 2 inches, data is collected at a continuous scan (speed of 0.2 Θ / sec). Example 1: 1:1:1 Ariu-Bitan L-proline acid water co-crystal 1.1 A 1:1:1 aprepitant L_proline acid water co-crystal is prepared as follows for the characteristic analysis 1:1:1 Aprepitant]^_proline acid eutectic batch: Aripiptan (300 mg) and L-proline (64.6 mg) were weighed into a glass vial. Add nitrate to the bottle. Methane (15 ml). The resulting slurry was placed in a shaker and aged for 5 days (from 201217366 to 5 Torr in an 8 hour cycle. 〇 'heated to 50 ° C for 4 hours and then The mixture was cooled to room temperature for an additional 4 hours. The product was then filtered in vacuo and the crystals obtained were dried overnight in a vacuum oven at 40 ° C. 1·2 —1:1:1 Aprepitant L脯XRpD Characterization of Amino Acid Water Co-crystals The XRpD pattern of the 1.1:1 aprepitant L_proline acid water co-crystal is not in Figure 1. The first table lists the angles. 20 ± 〇.2 20 and identified in the experimental XRPD pattern of Figure 1 The d_spacing of each peak. A complete list of peaks or a subset thereof may be sufficient to characterize the eutectic. For example, the eutectic may be characterized by a choice of 6.4, 9.4 '11.9, 12.9, 14.6, and 18· At least three peaks of 8° 2 (four)·2° 2 峰 peaks and XRPD patterns substantially similar to those of the graphs. Table 1 angle 2 Θ ± 0.2 ° 2 Θ d value angstrom strength % 6.4 13.80 27.90 7.6 11.65 9.80 9.4 9.37 28.30 10.0 8.83 6.20 11.9 7.45 96.80 12.2 7.22 10.10 12.9 6.88 37.30 13.5 6.55 23.70 13.8 6.42 12.90 14.6 6.05 70.90 15.3 5.80 22.60 16.1 5.50 6.70 16.8 5.27 6.40 17.5 5.06 40.50 18.0 4.91 47.50 18.8 4.70 31.60 19.4 4.58 96.50 20 201217366 20.0 4.43 62.10 20.6 4.32 82.60 21.2 4.18 100.00 21.5 4.12 18.90 21.7 4.10 15.70 22.8 3.90 17.10 23.1 3.85 16.30 23.4 3.81 22.50 23.7 3.75 10.00 24.0 3.70 9.00 24.3 3.66 20.90 24.7 3.60 17.40 24.9 3.57 10.00 25.7 3.46 6.20 25.9 3.43 12.20 26.4 3.38 13.00 26.9 3.31 16.00 27.2 3.28 6.00 27.7 3.22 9.50 28.1 3.17 6.40 28.4 3.14 5.80 29.2 3.05 6.00 29 .5 3.03 12.60 30.1 2.97 8.60 30.8 2.90 7.30 31.7 2.82 11.70 32.2 2.77 5.50 32.4 2.76 6.40 33.3 2.69 5.60 34.0 2.64 8.60 34.8 2.58 9.00 35.5 2.52 8.50 36.0 2.49 5.50 36.7 .2.45 5.10 37.3 2.41 9.50 38.7 2.33 4.30 38.9 2.31 5.70 39.9 2.26 4.80 21 201217366 1.3 Analysis of a 1:1:1 aprepitant L-proline acid water cocrystal The following crystals were prepared for the determination of single crystal structure: about 2 mg (visual estimate) prepared as described above The Tan L-proline aqueous eutectic batch was placed in a glass HPLC vial and 1 mL of nitrodecane was added. The sample was placed on a 5 °C shaker for about 3 minutes, then removed and quickly filtered into a clean glass vial. ,,, the film covers the vial and then pierces the film to allow slow evaporation and crystal formation. A suitable early crystal is isolated from the crystal formed by the method. The single crystal data and structural refinement parameters of the structure measured at 100 K are reported in Table 2 below. In the asymmetric unit of the crystal structure, there are two 1:1:1 molecules of aprepitant L_proline acid eutectic, and are labeled as molecule VIII and molecule B. The ORTEP pattern of a 1:1:1 aprepitant L-proline aqueous eutectic of molecules A and B is shown in Figures 2 and 3, respectively. Figure 2 is a diagram showing one of the numbering schemes used for the display of the molecule A of 1:1:1 aritipine L-proline acid water co-crystal at 100 K. Figure 3 is a graphical representation of one of the numbering schemes used for the display of the molecular B of the 1:1:1 aprepitant L-proline acid water co-crystal at 100 K. In Figures 2 and 3, the anisotropic atomic displacement ellipsoid system of non-hydrogen atoms is shown at a 50% probability level. The hydrogen atom is shown by an arbitrarily small radius. The 1:1:1 aprepitant L-proline acid water co-crystal at 100 κ, the hydrogen bond in dotted line, and the one-axis stacking diagram of the unit cell viewed downward, as shown in Fig. 4 . The XRPD pattern calculated based on the 1:1:1 aprepitant L-proline aqueous eutectic at 100 Å single crystal data and structure is shown in Figure 5. Also pay attention

22 201217366 To a small temperature shift in some peaks, the fact that the XRPD pattern calculated from the experimental XRPD pattern is collected at room temperature is derived from the data collected by 100 K. There is also a small difference in intensity due to the preferred orientation effects present in the experimental map. A slight difference can be observed between the ambient temperature experiment XRPD (Fig. 1) and the XRPD pattern (Fig. 5) calculated from the single crystal data of 100 K. A second set of SCXRD data for a 1:1:1 aprepitant L-proline aqueous eutectic was collected at an ambient temperature of about 294 K. The single crystal data and structural refinement parameters of the structure measured at 294K are reported in Table 3 below. In the asymmetric unit of the crystal structure, there is a single molecule of a 1:1:1 aprepitant L-proline aqueous eutectic. The ORTEP pattern of the 1:1:1 aprepitantine hydrous co-crystal is shown in Figure 6. Figure 6 is a plot of the numbering scheme used for the 1:1:1 Aprepitant L-proline aqueous eutectic molecule A at 294 K. An anisotropic atomic displacement ellipsoid system of non-hydrogen atoms is shown at a 30% probability level. The hydrogen atom is shown by an arbitrarily small radius. The L1:1 A. sultanate L-proline hydrate eutectic is shown in Figure 7 in a plot of 294 κ, a nitrogen bond on the dotted line, and a downward viewing of the unit cell. The crystal data presented in Tables 2 and 3 can also be used to characterize the 1:1:1 Aprepitant L-proline aqueous co-crystal of the present invention. The characteristic of the eutectic can be such as a parameter of its spatial group or its unit cell size, such as a corpse space at a temperature of about 294 K; or a = 9.l963 at a temperature of about 294 K (4 ^,6=12.8332(9^, e=27.4289(19^, a=90., β=9〇. and γ=90. unit cell size. 23 201217366 based on 1:1:1 aprepitant The XRPD pattern calculated from the single crystal data and structure of L-proline water eutectic at 294 K is shown in Figure 8. In this case, the experimental XRPD pattern collected at room temperature can be seen from 294 一致性 The calculated XRPD patterns derived from the collected data are in good agreement. There is a small difference in intensity due to the preferred orientation effect in the experimental map. The second molecular formula C28H32N5O6F7 molecular weight 667.59 crystal system monoclinic space Group P2\ unit cell size α=9.1229(2) angstrom 6=26.7988(5) angstrom c=12.6369(2) angstrom α=90° β=92.826(2)° γ=90° unit cell volume V=3085.75 ( 10) Cubic Angstrom 4 Temperature 100(1)Κ Radiation wavelength/type 1.54178/Cu/ia Number of reflections collected 28161 Number of reflections observed, (/&gt;2σ(/)) 26157 Resolution, maximum 2Θ, integrity 0.80 angstroms, 150.0°, 98.9% wi?2 (all data) 0.1176 R,(/&gt;2a(/)) 0.0421 Goodness of fit 1.007 Flack parameter -0.06(6) Residual density (maximum, minimum), e ang ° 0.450 ' -0.367 Form colorless rod 24 201217366 3rd formula C28H32N5O6F7 Molecular weight 667.59 Crystal system orthorhombic space group Ρ 2ι2, 2ι Early cell unit size α=9.1963(4)A6============================================================================================ 4 Temperature 294(1) K Radiation wavelength/type 1.54178/CuiCa Number of reflections collected 30624 Unique number of reflections 6588 Rint 0.0427 Number of reflections observed, (/&gt;2σ(7)) 5218 Resolution, maximum 2Θ, integrity 0.80 angstroms, 150.0., 99.4% w;?2 (all data) 0.1875 R, (/&gt; 2a(/)) 0.0568 Goodness of fit 1.005 Flack parameters 0.1 (2) Residual density (maximum, Minimum value), e angstrom θ 0.182, -0.169 form colorless rod shape

Differential scanning calorimetry (DSC) of 1.4:1:1 1:1 aprepitant L-proline acid eutectic DSC 1:1:1 aprepitant L-proline aqueous eutectic The trajectory is shown in Figure 9. A wide endotherm was observed in the temperature range of 125 to 170 ° C, followed by an endotherm of an initial temperature of 220.9 ° C and a maximum peak of 224.0 ° C. 25 201217366

1.5:1:1 1:1 Apremitan L-proline acid eutectic TGA In the thermogravimetric analysis (TGA) trace of Figure 10, the weight loss in the temperature range of 100 to 190 °C can be seen. It is 2.7%, which corresponds to 1 mole of water. 1.6 1:1:1 Aprepitant L-proline acid water co-crystal 1H NMR spectrum 1:1:1 aprepitant L-proline acid water co-crystal 1 Η NMR spectrum is shown in the first In the figure, it shows the following peaks: 1H NMR (400MHz, t/6-DMSO) δ: 11.30 (1Η), 7.86 (1Η), 7.51 (2Η), 7.37 (2Η), 7.08 (2Η), 4.94 (1Η ), 4.34 (1Η), 4.12 (1Η), 3.64 (1Η), 3.49 (1Η), 3.35 (1Η), 3.21 (1Η), 3.01 (1Η), 2.83 (1Η), 2.75 (1Η), 2.39 (1Η ), 1.97 (2Η), 1.73 (2Η) and 1.36 (3Η). The peak at 1.97 ppm in the 'H NMR spectrum corresponds to the two protons on the pyrrolidine ring of L-valine. A comparison of the peak integral with a peak at 7.86 ppm corresponding to an aromatic proton of aprepitant shows that the eutectic has Ari. Bittan: L-proline has a stoichiometry of 1:1. 1.7 1:1:1 Aprepitant L-proline acid water co-crystal Karl Fischer titration 1:1:1 Aristam L-proline acid water co-crystal Karl Fischer Snow analysis showed that the sample contained 2.9% water, which corresponds to 1.1 moles of water, consistent with the SCXRD structure showing one molecule of water per API molecule in the eutectic. 13C solid-state NMR characterization of 1.8:1:1 1:1 aprepitant L-proline acid eutectic using a 1 :1:1 aprepitant L-proline acid water co-crystal The 13C solid state NMR spectrum is shown in Figure 12. The “Dipole Dephasing” measurement system only 26 201217366 legacy signals from the fourth and sulphur-based carbon and any associated swaying sidebands. Table 4 lists the characteristic shifts observed in the experimental 13C NMR spectrum of Figure 12, ppm +/- 0.5 ppm. Table 4 Chemical Displacement ppm ± 0.500 ppm 175.7 161.2 158.2 148.0 145.7 133.2 132.2 131.5 123.8 24.3 1.9 Dissolution Study Using the US Pharmacopoeia Instrument 2, a 1:1:1 aprepitant L-脯 was examined in distilled water containing 2.2% SDS. The amino acid water co-crystals have a dissolution behavior in the test tube compared to the pure crystalline A. Table 5 contains the full details of the method used. A material providing I25 mg of aprepitant was used in each dissolution test, and the test samples in each experiment were directly added to the dissolution medium in the form of a loose powder. Table 5 Instrument USP Type II (leaf solution 2.2% of the dissolved medium in purified water (ml) 900 '------..-- Medium temperature 37.0〇C±0.5〇C - speed (rPm) 100 —.................Between (minutes) Bu 2, 3, 4, 5, 1〇, 15, 20, —$13⁄4^ (minutes) 180 --' ................. --^ Samples at 5 hours each time, ----~----- 27 201217366 Using Agilent with UV variable wavelength detection ( Agilent) 1100/12〇0 series HPLC system, analyzed by HPLC/Uv. Details of the HPLC method used are shown in Table 6. 0.14 mg/ml standard was prepared in acetonitrile. The sample solution was filtered through a 0.45 micron filter. Table 6 Mobile Phase A 0.1% in purified water TFA Mobile phase B 0.085% in acetonitrile TFA Column Phenomenex Luna C 18(2) 50x4.6 mm, 3 micron column temperature 25 °C flow rate 2.0 ml/min injection volume 5 microliters wavelength 260 nm run time 4.4 minutes gradient program time (minutes) %A %B 0 95 5 1 80 20 2.3 5 95 3.3 5 95 3.5 95 5 4.4 9 5 5 The dissolution test of a 1: 1:1 aprepitant L-proline aqueous eutectic with pure aprepitant was carried out in a three-fold manner. The average dissolved value obtained at different time points is shown in the sixth In the table, Figure 13 illustrates the average dissolution profile of the 1:1:1 1:1 aprepitant L-proline aqueous eutectic and the pure Ari &quot;Bitan observed during the first 30 minutes. As can be seen from Table 7, under these test conditions, the eutectic had dissolved more than 93° in 1 minute. The pure API dissolved only 18.5% at this time. As a result, pure crystalline aprepitant was found. Almost until the end of the dissolution experiment

28 201217366 (180 minutes) to achieve the same level of dissolution that the eutectic achieved during the first minute of the study. This dissolution study shows that the 1:1:1 aprepitant L-proline eutectic crystal exhibits a rapid dissolution rate under these conditions, and the eutectic remains in solution upon dissolution and under these conditions. There is no reprecipitation of the API, which indicates that a 1:1:1 aprepitant L-proline aqueous co-crystal can be used to prepare a liquid pharmaceutical formulation. Table 7 time (minutes) 1:1:1 aprepitant L-valine eutectic (156 mg) crystalline aprepitant (125 mg) 0 0.0 0.0 1 93.4 18.5 2 95.7 34.4 3 95.6 44.2 4 95.8 52.2 5 95.1 57.6 10 95.5 70.1 15 95.9 77.2 20 96.0 80.4 30 96.2 85.4 45 96.8 87.3 60 97.0 89.3 180 99.2 94.6 1.10: Stability study for stability studies, thus a 1:1:1 aprepitant L - The proline acid water co-crystals are dissociated from time to time as their starting components under accelerated conditions, and their physical stability is examined. An equal amount of 1:1:1 aprepitant L-proline aqueous eutectic was placed in 7 clear glass vials. These glass vials are loosely sealed with a plastic screw cap to provide a barrier to solids transfer, but still allow for a moisture balance with the outside environment. The vial is at the top of the sample. 29 201217366 The space is estimated to exceed 95% of the total volume of the vial. All 7 samples were placed on a tray and stored in a stability cabinet at 40 ° C / 75% relative humidity. Individual samples were taken at predetermined time points as shown in Table 8, and examined by XRPD. The XRPD pattern obtained at each time point was characterized by a 1:1:1 aprepitant L-proline aqueous co-crystal without evidence of any starting material. Figure 14 illustrates the XRPD pattern obtained at time points 0, 3 and 6 months. Figure 14 is an XRPD pattern of the 1:1:1 aprepitant L-proline aqueous eutectic at these time points during the accelerated stability study at 40 ° C / 75% relative humidity for 6 months. Overlay. It can be seen that there is no significant change in the sample during the six periods and no evidence of dissociation becomes any starting material, which indicates that the 1:1:1 aprepitant L-proline acid water co-crystal is in these Stability under conditions. Table 8 Time point XRPD characteristic analysis 0 eutectic 1 week eutectic 2 weeks eutectic 3 weeks eutectic 1 month eutectic 2 months co-crystal 3 months co-crystal 6 months co-crystal 2nd case: The optional preparation of a 1:1:1 aprepitant L-proline aqueous eutectic was also prepared as follows: a 1:1:1 aprepitant L-proline aqueous co-crystal: aprepitant (500 mg) and L-proline (107.7 mg) were weighed into a glass vial. Acetonitrile (2.5 ml) and water (0.5 ml) were added to the bottle. The resulting slurry was placed in a shaker and aged for 3 days (from room temperature to 50 ° C in an 8 hour cycle, heated to 50 ° C for 4 hours and then cooled to room temperature at another 4 hours 30 201217366) ). The product was then filtered under vacuum and allowed to dry overnight under ambient conditions. XRPD analysis confirmed that the product was identical to a 1:1:1 Aribi-Bantan-proline acid water co-crystal. [_ style simple description]

Figure 1 shows an XRPD pattern of a 1:1:1 aprepitant L-proline aqueous co-crystal. Figure 2 shows the ORTEP plot of the molecular octet of the 1:1:1 Ari-Bantan L-proline acid eutectic crystal at 100K.

Figure 3 shows the ORTEP plot of the molecular B of the 1:1:1 Ade-Butan L-proline acid water co-crystal at 100K. Figure 4 shows Ari in 1:1. Bitan L-proline water co-crystals are deposited in the ancestors. Figure 5 shows the XRPD pattern calculated from the 1:1:1 Ari 0-tan L-proline eutectic crystal. Figure 6 shows the ORTEP plot of the 1:1:1 Arigubitan L-proline eutectic in the fox.

_ Airf repinitan L-proline acid water co-crystal at 294K Figure 7 shows a 1:1:1 accumulation of A secret. The calculated XRPD pattern of a 1 1 1 aprepitant L-proline acid water co-crystal at 294 Torr. Figure 9 shows a 1:1:1 Curry

. DSC of Bittan L-proline water eutectic

The TGA trace of repinitan L-proline acid eutectic. Figure 10 shows the 1:1:1 trajectory. 31 201217366 Figure 11 shows the 1 NMR spectrum of 1:1:1 aprepitant L-proline acid water co-crystal. Figure 12 shows the 13C solid state NMR spectrum of a 1:1:1 aprepitant L-proline aqueous co-crystal recorded using dipole phase desorption. Figure 13 shows the average dissolution profile of a 1:1:1 aprepitant L-proline aqueous eutectic and crystalline aprepitant during the first 30 minutes in distilled water containing 2.2% S D S . Figure 14 shows a stack of XRPD patterns at different time points during the accelerated stability study of 1:1:1 aprepitant L-proline acid eutectic at 40 ° C / 75% relative humidity for 6 months. Figure. [Main component symbol description] (none) 32

Claims (1)

201217366 VII. Patent application scope: 1. A 1:1:1 aprepitant L-proline acid water co-crystal. 2. An aprepitant L-proline aqueous eutectic characterized by at least one of the following: having a peak selected from the group consisting of 6.4, 9.4, 11.9, 12.9, 14.6, 18.8, and 2 s. a powder X-ray diffraction pattern of at least three of the peaks; a powder X-ray diffraction pattern substantially similar to Figure 1; a corpse 212121 space group at a temperature of about 294 ;; or α at a temperature of about 294 = 9.1963 (4) angstrom, office = 12.83232 (9) angstrom, c = 27.4289 (19) angstrom, α = 90 °, β = 90 ° and γ = 90 ° unit cell size. 3. A pharmaceutical composition comprising a 1: 1:1 aprepitant L-proline aqueous co-crystal and a pharmaceutically acceptable carrier as claimed in claim 1 or 2. 4. A method of treating or preventing a condition associated with D-zone vomiting, a neuropsychiatric disorder, an inflammatory disease, pain, cancer, a skin disease, itch, a respiratory disease, an addiction, the steps including A patient in need is administered a therapeutically effective amount of aprepitant L-proline aqueous co-crystal as claimed in Patent Application No. 1 or 2: 1:1:1. 5 - A method for treating or preventing a condition associated with 11 area vomiting, a neuropsychiatric disease, an inflammatory disease, pain, cancer, a skin disease, itching, a respiratory disease, an addiction, the steps of which include A therapeutically effective amount of a pharmaceutical composition as disclosed in claim 3, paragraph 3, 201217366, is administered to a patient in need thereof. 6. A 1:1:1 aprepitant L-proline aqueous eutectic crystal in the treatment or prevention and vomiting, a neuropsychiatric inflammatory disease, pain, cancer, as claimed in claim 1 or 2. A use of a skin disease, a snoring disease, a respiratory disease, or an addiction-related disorder. 7. As claimed in the third paragraph of the patent application, the pharmaceutical composition is used in the treatment or prevention of vomiting, neuropsychiatric diseases, inflammatory diseases, pain, cancer, a skin disease, pruritus, and a respiratory system. The use of disease, an addiction-related disorder. 8. A ruthenium citrate L-proline hydrate of 1.1.1. 9. A pharmaceutical composition comprising aspirin L-proline hydrate as described in claim 8 of the patent application and a pharmaceutically acceptable carrier. 10. A method of treating or preventing a condition associated with vomiting, a neuropsychiatric disease, an inflammatory disease, pain, cancer, a skin disease, a pruritus, a respiratory disease, an addiction disorder, the steps of which include For the required-patient administration-therapeutic effective amount, aprepitant L-proline hydrate, as claimed in the patent scope: 1:1:1. U. A method for treating or preventing a disorder associated with a package, a neuropsychiatric disease, an inflammatory disease, pain, cancer, a skin disease, a itch, a respiratory disease, or an addiction disorder, The steps comprise administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 9 of the patent application. Π. For example, the 1:1:1 Ariqin l_proline hydrate in the scope of patent application is in the treatment or rib and bag, the sect of the spirit, the inflammatory 34 201217366 disease, pain, cancer , the use of skin diseases, itching, a respiratory disease, an addiction-related disorder. 13 · The pharmaceutical composition of claim 9 of the scope of the patent application is in the treatment or prevention of vomiting, neuropsychiatric diseases, an inflammatory disease, pain, cancer, a skin disease, itching, a respiratory disease, The use of an addiction-related disorder. 35